The cyclic tetradecapeptide somatostatin-14 (SRIF) was originally isolated from the hypothalamus and characterized as a physiological inhibitor of growth hormone (GH) release from the anterior pituitary. This tetradecapeptide has a bridging or cyclizing bond between the sulfhydryl groups of the two cysteinyl amino acid residues in the 3- and 14-positions. SRIF and SRIF-related analogs affect multiple cellular processes, specifically those related to GH release, and also inhibit the growth of certain tumors. The analog [D-Trp8]-SRIF, for example, has the amino acid sequence: (cyclo 3-14) H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH, and has a much greater potency to inhibit release of GH than SRIF.
SRIF induces its biological effects by interacting with a family of membrane-bound, structurally-similar receptors. Five SRIF receptors have been cloned and are referred to as SSTR 1-5. All five receptors bind SRIF and the 28 amino acid SRIF peptide, SRIF-28 (from porcine gastro-intestinal tract and porcine and ovine hypothalamus), with high affinity. Agonists and antagonists for the various SSTR's have been identified.
Somatostatin peptides and analogs can be modified to allow for selective binding of individual SSTRs. Such peptides and analogs are useful, for example, in differentiating the individual signaling functions of the individual receptors. The use of receptor-specific peptides and analogs have led to the notion that different receptor subtypes mediate distinct functions of SRIF in the body.
Agonists selective for SSTR2 and SSTR5, for example, have been identified and used to reveal distinct functions of these receptors. These two receptors are believed to be the predominant subtypes in peripheral tissues. SSTR2 is believed to mediate the inhibition of growth hormone, glucagon and gastric acid secretion. Octreotide, an agonist, shows some specificity for SSTR2. SSTR5, by contrast, appears to be primarily involved in the control of insulin and amylase release. Analogs have been described that have specificity for SSTR2 and SSTR5, respectively.
SSTR3 mediates inhibition of gastric smooth muscle contraction. Somatostatin analogs that bind specifically to SSTR3 are known.
SSTR4 is found in the pituitary, lungs, GI tract, kidneys and certain tumors to the substantial exclusion of the other SRIF receptors. It is believed to be activated upon binding by SRIF. SSTR4- and SSTR1-specific ligands have been used, for example, in methods for treating endothelial cells. Receptor-selective somatostatin peptide analogs that are specific to SSTR4 are known in the art.
Somatostatin receptors are expressed in pathological states, particularly in neuroendocrine tumors of the gastrointestinal tract. Most human tumors originating from the somatostatin target tissue have conserved somatostatin receptors. The effect of somatostatin signaling was first observed in growth hormone-producing adenomas and TSH-producing adenomas; about one-half of endocrine inactive adenomas display somatostatin receptors. Ninety percent of the carcinoids and a majority of islet cell carcinomas, including their metastasis, usually have a high density of somatostatin receptors. Only 10 percent of colorectal carcinomas and none of the exocrine pancreatic carcinomas contain somatostatin receptors, however. The somatostatin receptors in tumors can be identified, for example, using in vitro binding methods or using in vivo imaging techniques; the latter allow the precise localization of the tumors and their metastasis in the patients. Because somatostatin receptors in gastroenteropancreatic tumors are functional, their identification can be used to assess the therapeutic efficacy of an analog to inhibit excessive hormone release in the patients.
In light of their use as diagnostic and therapeutic targets, there is a need for somatostatin peptide antagonists that bind strongly to SSTR2, while at the same time showing only minimal propensity for binding to the other four receptors. For use as diagnostic imaging agents, such antagonists would have an advantage over SSTR2-selective agonists in that the antagonists would preferably not be internalized.